WO2014023647A1 - Esters de bortézomib et formulations de ceux-ci - Google Patents
Esters de bortézomib et formulations de ceux-ci Download PDFInfo
- Publication number
- WO2014023647A1 WO2014023647A1 PCT/EP2013/066224 EP2013066224W WO2014023647A1 WO 2014023647 A1 WO2014023647 A1 WO 2014023647A1 EP 2013066224 W EP2013066224 W EP 2013066224W WO 2014023647 A1 WO2014023647 A1 WO 2014023647A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- bortezomib
- tartrate
- bis
- tartaric acid
- solution
- Prior art date
Links
- 0 CC(C)CC(BOC(C(O)=CO)=O)NC(C(Cc1ccccc1)NC(C1N=*C=N1)=O)=O Chemical compound CC(C)CC(BOC(C(O)=CO)=O)NC(C(Cc1ccccc1)NC(C1N=*C=N1)=O)=O 0.000 description 1
- GXJABQQUPOEUTA-LWKPJOBUSA-N CC(C)C[C@@H](B(O)O)NC(C(Cc1ccccc1)NC(c1nccnc1)=O)=O Chemical compound CC(C)C[C@@H](B(O)O)NC(C(Cc1ccccc1)NC(c1nccnc1)=O)=O GXJABQQUPOEUTA-LWKPJOBUSA-N 0.000 description 1
- NPXUCNSCOOQOHO-SCDLOJPASA-N CC(C)C[C@@H](B(O[C@@H]1[C@@H](C(O)=O)O)OC1=O)NC(C(Cc1ccccc1)NC(c1nccnc1)=O)=O Chemical compound CC(C)C[C@@H](B(O[C@@H]1[C@@H](C(O)=O)O)OC1=O)NC(C(Cc1ccccc1)NC(c1nccnc1)=O)=O NPXUCNSCOOQOHO-SCDLOJPASA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/04—Esters of boric acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
- C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
- C07K5/06—Dipeptides
- C07K5/06008—Dipeptides with the first amino acid being neutral
- C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- the present invention relates to bortezomib esters, more particularly to bortezomib esters with tartaric acid, and to stable formulations containing them.
- Bortezomib belongs to the therapeutic class of proteasome inhibitors, a cellular protein complex having the function of degrading the proteins to be eliminated.
- the inhibitory effect of bortezomib on proteasome interferes with the intracellular processes for protein turnover, with the consequent beginning of a degenerative state of the cell leading to its death.
- bortezomib has been approved for the treatment of forms of multiple myeloma which were already treated with at least another therapeutic agent.
- the active ingredient is on the market under the tradename Velcade ® as lyophilized powder containing mannitol esters of bortezom ib which is adm in istered by intravenous route after reconstitution of the lyophilizate with physiologic solution where the active ingredient is reconstituted by hydrolysis.
- bortezomib as lyophylized powder consisting of its mannitol esters was developed to overcome the difficulties due to the poor water solubility of the active ingredient as such and to its instability.
- bortezomib as lyophilized mannitol esters allows to obtain a powder which is stable also after 18 months when stored at 5°C, 37°C or 50°C: said powder, after reconstitution with a NaCI 0.9% solution to be administered intravenously, dissolves within 10 seconds resulting in a clear colorless solution containing the active ingredient as boronic acid obtained by complete hydrolysis of the ester.
- WO2009154737 discloses esters of bortezomib with a-hydroxycarboxylic acids, in particular citric acid, and their formulations.
- WO2010039762 discloses liquid formulations of bortezomib in an organic solvent.
- WO2010089768 discloses a bortezomib formulation wherein the active ingredient is lyophilized with tromethamol.
- WO20101 14982 discloses lyophilized containing bortezomib, cyclodextrin and at least a filler or a surfactant.
- US201 10230441 discloses a liquid formulation of bortezomib wherein the solvent is mainly propylen glycol.
- bortezomib esters in particular bortezomib esters with tartaric acid wherein bortezomib and tartaric acid are in 2:1 molar ratio which allow to obtain particularly stable and soluble formulations.
- object of the present invention are bortezomib esters with tartaric acid wherein bortezomib and tartaric acid are in molar ratio 2: 1 , and in particular the bortezomib esters of formula (III) and formula (IV)
- tartaric acid means L-tartaric acid, D- tartaric acid or meso-tartaric acid.
- bortezomib-tartrate 2 1 esters (also called bis-bortezomib tartrate) object of the present invention will be also indicated as:
- esters object of the present invention formu lated i n com bi nation with pharmaceutically acceptable excipients, result in stable formulations which can be reconstituted with physiologic solution to obtain injectable clear solutions containing bortezomib as active ingredient.
- a further object of the present invention are formulations of esters of bortezomib with tartaric acid wherein bortezomib and tartaric acid are in a molar rati o 2 : 1 , i n particu la r of esters of form u la I I I a n d IV, in adm ixture with pharmaceutically acceptable excipients and the injectable solutions obtained by reconstituting said formulations with physiologically compatible solutions.
- esters of bortezomib with tartaric acid object of the present invention are prepared by reacting bortezomib, preferably bortezomib boroxine, with tartaric acid or a salt thereof.
- the bortezomib esters of formula III object of the present invention are prepared by reacting tartaric acid , preferably L-tartaric acid , and bortezomib, preferably bortezomib boroxine, in a suitable solvent according to the following scheme wherein the reaction with L-tartaric acid is depicted:
- bortezomib is isolated as trimeric form (boroxine) and therefore the esters of formula III object of the present invention are prepared by reacting two moles of boroxine with three moles of tartaric acid.
- (5+5) bis-bortezomib tartrate III is prepared by reacting boroxine and L-tartaric acid.
- Boroxine is dissolved in a suitable organic solvent and L-tartaric acid, optionally dissolved in a suitable organic acid, is added to the resultant solution.
- the resultant solution is concentrated under vacuum up to a solid residue or added with a suitable co-solvent obtaining the solid by precipitation.
- the resultant solid product is isolated and dried under vacuum obtaining (5+5) bis-bortezomib tartrate III with high purity.
- suitable solvents are alcohols, such as Ci -3 alcohols, for example methanol, ethanol and isopropanol, ketones, for example acetone and methylethylketone, alkyl halides, for example dichloromethane and chloroform, esters, for example ethyl acetate and isopropyl acetate, or nitriles, for example acetonitrile and propionitrile.
- alcohols such as Ci -3 alcohols, for example methanol, ethanol and isopropanol
- ketones for example acetone and methylethylketone
- alkyl halides for example dichloromethane and chloroform
- esters for example ethyl acetate and isopropyl acetate
- nitriles for example acetonitrile and propionitrile.
- the molar ratio between boroxine and the used tartaric acid is 0.67 ⁇ 0.05 coresponding to a molar ratio between boronic acid and tartaric acid from 1.9 to 2.2. (5+5) bis-bortezomib tartrate III is isolated in a particularly pure form, generally with purity > 99.5%.
- the bortezomib esters of formula IV object of the present invention are prepared by reacting tartaric acid salts, preferably sodium salts, and bortezomib, preferably bortezom ib boroxi ne, i n a suitable solvent accord i ng to the fol lowi ng scheme wherein the reaction with L-tartaric acid sodium salt is depicted:
- bortezomib is isolated as trimeric form (boroxine) and therefore the esters of formula IV object of the present invention are prepared by reacting two moles boroxine with three moles tartaric acid sodium salt.
- (6+6) bis-bortezomib tartrate IV is prepared by reacting boroxine and L-tartaric acid sodium salt. Boroxine is dissolved in a suitable organic solvent and L-tartaric acid sodium salt, optionally dissolved in a suitable organic acid, is added to the resultant solution. The resultant solution is concentrated under vacuum up to a solid residue or added with a suitable co-solvent obtaining the solid by precipitation. The resultant solid product is isolated and dried under vacuum obtaining (6+6) bis-bortezomib tartrate IV with high purity.
- suitable solvents are alcohols, such as Ci -3 alcohols, for example methanol, ethanol and isopropanol, ketones, for example acetone and methylethylketone, alkyl halides, for example dichloromethane and chloroform, esters, for example ethyl acetate and isopropyl acetate, or nitriles, for example acetonitrile and propionitrile.
- alcohols such as Ci -3 alcohols, for example methanol, ethanol and isopropanol
- ketones for example acetone and methylethylketone
- alkyl halides for example dichloromethane and chloroform
- esters for example ethyl acetate and isopropyl acetate
- nitriles for example acetonitrile and propionitrile.
- the molar ratio between boroxine and the used tartaric acid salt is 0.67 ⁇ 0.05 corresponding to a molar ratio between boronic acid and tartaric acid from 1 .9 to (6+6) bis-bortezomib tartrate IV is isolated in a particularly pure form, generally with purity > 99.5%.
- the compound of formula IV shows different polymorphic forms and an amorphous form.
- Thickness of the filter (mm) 0.020
- Control software of the instrument XPERT-PRO vs. 1 .9B
- Form A is obtained as described in example 5 and shows a PXRD with peaks at 9.94, 14.37, 15.66, 19.02, 19.80, 24.65, 25.57, 26.82, 30.32, 31 .37, 32.12, 33.75, 34.30, 36.29 and 38.98 ⁇ 0.20 2theta.
- Form B of (6+6) bis-bortezomib tartrate of formula IV is an object of the present invention.
- Form B is obtained as described in example 6 and shows a PXRD with peaks at 3.39, 5.77 , 6.69, 8.09, 8.78, 9.31 , 10.03, 18.71 , 19.12, 23.29 and 23.59 ⁇ 0.20 2th eta.
- Amorphous form of (6+6) bis-bortezomib tartrate of formula IV is an object of the present invention.
- the compound bortezomib tartrate 1 :1 is obtained as main product in admixture with a dimeric species for which no characterization is given.
- the compounds of formula I I I and IV object of the present invention are obtained with high purity by reacting boroxine with tartaric acid and by reacting boroxine with a tartaric acid salt respectively, and their structure has been characterized as (5+5) bis-bortezomib tartrate of formula III and (6+6) bis-bortezomib tartrate of formula IV.
- the compounds object of the present invention when formulated in combination with pharmaceutically acceptable excipients, result in stable formulations.
- Said formulations can be solid , for example physical mixtures of powders or lyophilized powders, or liquid, for example concentrated solutions in a suitable organic solvent optionally added with suitable excipients and/or stabilizing agents.
- Suitable solid formulations are those obtained by making a solid mixture of a compound object of the present invention with mannitol or inorganic salts or by lyophilizing a mixture of a compound according to the present invention with mannitol or inorganic salts.
- Suitable liquid formulations are concentrated solutions of a compound according to the present invention in dimethylsulfoxide optionally added with suitable excipients and/or stabilizing agents.
- the stability of the compounds object of the present invention and of the formulation containing them has been evaluated through stability tests under ICH storage (25°C, 60% relative humidity) and accelerated (40°C, 75% relative humidity) conditions by collecting the HPLC purity data of the tested formulations after two and four weeks. Under all the evaluation conditions, the stability resulted at least comparable with the known formulations, in particular with the formulations described in US 6,958,319.
- the formulations object of the present invention are also characterized by a very good solubility in water or aqueous solutions. Once reconstituted with physiologically compatible aqueous solutions, they give rise in short time, generally within one or two min utes, to clear aq ueous solutions wherein bis-bortezomib tartrate is completely hydrolyzed to give the corresponding boronic acid and tartaric acid.
- the concentrated liquid formulations of bis-bortezomib tartrate in a suitable pharmaceutically acceptable organic solvent are particularly suitable to obtain sterile injectable formulations wherein the active ingredient bortezomib is reconstituted as free boronic acid in solution by adding a suitable amount of a physiologically compatible aqueous solution.
- a suitable pharmaceutically acceptable organic solvent for example dimethylsulfoxide
- Boroxine used in the experiments described herein after was prepared according to the procedures described in WO2005097809. The characterization of boroxine by
- the DSC were carried out under the following conditions:
- Heating and cooling speed 0.01 K/min ... 50 K/min
- Atmosphere inert (nitrogen)
- Gas flow control 2 cleaning gasses and 1 protecting gas Cleaning gas: nitrogen
- HPLC method used for the purity analysis was the following:
- a xc peak area of the impurity in the sample
- the mother solution (38 g/l) and the diluted 1 :1 solution (19 g/l) were put into glass vials with screw cap and hermetic closure and undergone stability tests under the following conditions:
- micronized product was analyzed by using mastersizer Microplus (Malvern) through LALLS technique using silicone oil as dispersing medium.
- a micronized product prepared as described in example 1 8 was mixed with NaH 2 P0 4 Na 2 HP0 4 and with disodium tartrate.
- HPO4 separately >300 sec 1 : 1 weighed in vial
Abstract
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CA2876454A CA2876454A1 (fr) | 2012-08-06 | 2013-08-01 | Esters de bortezomib et formulations de ceux-ci |
US14/419,493 US9206229B2 (en) | 2012-08-06 | 2013-08-01 | Bortezomib esters and formulations thereof |
EP13756835.8A EP2880040A1 (fr) | 2012-08-06 | 2013-08-01 | Esters de bortézomib et formulations de ceux-ci |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
ITMI2012A001394 | 2012-08-06 | ||
IT001394A ITMI20121394A1 (it) | 2012-08-06 | 2012-08-06 | Esteri di bortezomib e loro formulazioni |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2014023647A1 true WO2014023647A1 (fr) | 2014-02-13 |
Family
ID=47016769
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP2013/066224 WO2014023647A1 (fr) | 2012-08-06 | 2013-08-01 | Esters de bortézomib et formulations de ceux-ci |
Country Status (5)
Country | Link |
---|---|
US (1) | US9206229B2 (fr) |
EP (1) | EP2880040A1 (fr) |
CA (1) | CA2876454A1 (fr) |
IT (1) | ITMI20121394A1 (fr) |
WO (1) | WO2014023647A1 (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3324936B1 (fr) | 2015-07-22 | 2022-09-28 | STADA Arzneimittel AG | Procédé de préparation d'une solution d'ester de bortezomib |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009154737A1 (fr) * | 2008-06-17 | 2009-12-23 | Millennium Pharmaceuticals, Inc. | Composés de borates esters et compositions pharmaceutiques contenant des composés |
-
2012
- 2012-08-06 IT IT001394A patent/ITMI20121394A1/it unknown
-
2013
- 2013-08-01 US US14/419,493 patent/US9206229B2/en not_active Expired - Fee Related
- 2013-08-01 EP EP13756835.8A patent/EP2880040A1/fr not_active Withdrawn
- 2013-08-01 CA CA2876454A patent/CA2876454A1/fr not_active Abandoned
- 2013-08-01 WO PCT/EP2013/066224 patent/WO2014023647A1/fr active Application Filing
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2009154737A1 (fr) * | 2008-06-17 | 2009-12-23 | Millennium Pharmaceuticals, Inc. | Composés de borates esters et compositions pharmaceutiques contenant des composés |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP3324936B1 (fr) | 2015-07-22 | 2022-09-28 | STADA Arzneimittel AG | Procédé de préparation d'une solution d'ester de bortezomib |
Also Published As
Publication number | Publication date |
---|---|
EP2880040A1 (fr) | 2015-06-10 |
US9206229B2 (en) | 2015-12-08 |
ITMI20121394A1 (it) | 2014-02-07 |
CA2876454A1 (fr) | 2014-02-13 |
US20150232508A1 (en) | 2015-08-20 |
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